Discovery of 2H-chromone-4-one based sulfonamide derivatives as potent retinoic acid receptor-related orphan receptor γt inverse agonists.

Retinoic acid receptor related orphan receptor γt (RORγt), identified as the essential functional regulator of IL-17 producing Th17 cells, is an attractive drug target for treating autoimmune diseases. Starting from the reported GSK2981278 (Phase II), we structurally modified and synthesized a series of 2H-chromone-4-one based sulfonamide derivatives as novel RORγt inverse agonists, which significantly improved their human metabolic stabilities while maintaining a potent RORγt inverse agonist profile. Efforts in reducing the lipophilicity and improving the LLE values led to the discovery of c9, which demonstrated potent RORγt inverse agonistic activity and consistent metabolic stability. During in vivo studies, oral administration of compound c9 exhibited a robust and dose-dependent inhibition of IL-17A cytokine expression and significantly lessened the skin inflammatory symptoms in the mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that c9 can suitably occupy the active pocket, and the introduction of the morpholine pyridine group can interact with Leu396, His479, and Cys393. Thus, compound c9 was selected as a preclinical compound for treating Th17-driven autoimmune diseases.

[Application of partial internal sphincter myomectomy in patients with Hirschsprung disease undergoing transanal one-stage pull-through operation].

OBJECTIVE: To investigate the effect of partial internal sphincter myomectomy on transanal one-stage pull-through operation for Hirschsprung disease (HD). METHODS: A prospective group of 153 pediatric patients with HD in Guangdong Dongguan People's Hospital between 2003-2012 were enrolled, who underwent transanal one-stage pull-through operation. Children were divided into partial resection group (77 cases) undergoing partial internal sphincter myomectomy and simple incision group (76 cases) undergoing simply internal sphincter dissection, respectively. Differences of postoperative complications and continence between two groups were compared. RESULTS: Postoperative complications such as rectal muscularis infection [1.3% (1/77) vs. 11.8% (9/76), P<0.05], enterocolitis [2.6% (2/77) vs. 13.2% (10/76), P<0.05], anastomosis stenosis[3.9% (3/77) vs. 22.4% (17/76), P<0.01] and abdominal distension [10.4% (8/77) vs. 25.0% (19/76), P<0.05] were lower in partial resection group as compared to simple incision group. The time of antibiotics administration was also lower in partial resection group [(3.9±1.1) d vs. (4.6±1.1) d, P<0.01]. Difference in the continence between the two groups was not statistically significant (kelly score, 5.1±0.5 vs. 5.2±0.6, P>0.05). CONCLUSIONS: Compared with simply internal sphincter dissection in operation, partial internal sphincter myomectomy with transanal one-stage pull-through operation for HD can reduce the postoperative complications and does not increase the damage of the continence.